Dutasteride

Last updated

Dutasteride
Dutasteride.svg
Clinical data
Trade names Avodart, others
Other namesGG-745; GI-198745; GI-198745X; N-[2,5-Bis(trifluoromethyl)phenyl]-3-oxo-4-aza-5α-androst-1-ene-17β-carboxamide
AHFS/Drugs.com Monograph
MedlinePlus a603001
License data
Pregnancy
category
  • Not to be used during pregnancy
Routes of
administration 		By mouth
Drug class 5α-Reductase inhibitor
ATC code
Legal status
Legal status
Pharmacokinetic data
Bioavailability 60% [1]
Protein binding 99% [1]
Metabolism Liver (CYP3A4) [1]
Metabolites • 4'-Hydroxydutasteride [1]
• 6'-Hydroxydutasteride [1]
• 1,2-Dihydrodutasteride [1]
(All three active) [1]
Elimination half-life 4–5 weeks [2] [3]
Excretion Feces: 40% (metabolites) [1]
Urine: 5% (unchanged) [1]
Identifiers
  • (1S,3aS,3bS,5aR,9aR,9bS,11aS)-N-[2,5-bis(trifluoromethyl)phenyl]-9a,11a-dimethyl-7-oxo-1,2,3,3a,3b,4,5,5a,6,9b,10,11-dodecahydroindeno[5,4-f]quinoline-1-carboxamide
CAS Number
PubChem CID
IUPHAR/BPS
DrugBank
ChemSpider
UNII
KEGG
ChEBI
ChEMBL
CompTox Dashboard (EPA)
ECHA InfoCard 100.166.372 OOjs UI icon edit-ltr-progressive.svg
Chemical and physical data
Formula C27H30F6N2O2
Molar mass 528.539 g·mol−1
3D model (JSmol)
  • FC(F)(F)c1cc(c(cc1)C(F)(F)F)NC(=O)[C@@H]3[C@]2(CC[C@H]4[C@H]([C@@H]2CC3)CC[C@H]5NC(=O)\C=C/[C@]45C)C
  • InChI=1S/C27H30F6N2O2/c1-24-11-9-17-15(4-8-21-25(17,2)12-10-22(36)35-21)16(24)6-7-19(24)23(37)34-20-13-14(26(28,29)30)3-5-18(20)27(31,32)33/h3,5,10,12-13,15-17,19,21H,4,6-9,11H2,1-2H3,(H,34,37)(H,35,36)/t15-,16-,17-,19+,21+,24-,25+/m0/s1 Yes check.svgY
  • Key:JWJOTENAMICLJG-QWBYCMEYSA-N Yes check.svgY
   (verify)

Dutasteride, sold under the brand name Avodart among others, is a medication primarily used to treat the symptoms of a benign prostatic hyperplasia (BPH), an enlarged prostate not associated with cancer. A few months may be required before benefits occur. [4] It is also used for scalp hair loss in men and as a part of hormone therapy in transgender women. [5] [6] It is usually taken by mouth. [7] [8] [4]

Contents

The most commonly reported side effects of dutasteride, although rare, include sexual dysfunction and depression. [7] In the largest available study of 6,729 men with BPH, 9% experienced erectile dysfunction (compared to 5.7% treated with a placebo), 3.3% experienced decreased sex drive (vs 1.6% of placebo), and 1.9% had enlarged breasts (vs 1% of placebo). [9] [10] Exposure during pregnancy is specifically contraindicated because antiandrogens such as dutasteride have been shown to interfere with the sexual development of male fetuses. [3] [7]

Dutasteride was patented in 1993 by GlaxoSmithKline and was approved for medical use in 2001. [11] [7] In the United States and elsewhere, it is available as a generic medication. [4] In 2018, it was the 291st-most commonly prescribed medication in the US with more than 1 million prescriptions. [12]

Medical uses

Benign prostatic hyperplasia and prostate cancer

Dutasteride is used for treating BPH, colloquially known as an "enlarged prostate". [8] [13] It is approved by the Food and Drug Administration (FDA) in the U.S. for this indication. [14] A 2010 Cochrane review found a 25–26% reduction in the risk of developing prostate cancer with 5α-reductase inhibitor chemoprevention. [15]

Scalp hair loss and excessive hair growth

Dutasteride is approved for the treatment of male androgenetic alopecia in South Korea and Japan at a dosage of 0.5 mg per day. [5] [16] Several studies have found it to induce hair regrowth in men more rapidly and to a greater extent than even the highest approved dosage of finasteride. [5] [17] [18] [19] The superior effectiveness of dutasteride relative to finasteride for this indication is because the inhibition of 5α-reductase and consequent reduction of dihydrotestosterone (DHT) production within the hair follicles is more complete with dutasteride. Dutasteride is also used off-label in the treatment of female pattern hair loss. [20] [21]

Other 5α-reductase inhibitors such as finasteride (a type 2 inhibitor) have been used off-label to treat excessive hair growth in women with hirsutism. [3] [22] Since dutasteride is an inhibitor of both type 1 and 2 5α-reductases, it could theoretically be a more effective therapy for hirsutism. However, dutasteride is not recommended for this indication due to a lack of supportive clinical evidence and a substantial risk of birth defects in female patients who inadvertently become pregnant. [22] [23]

Transgender hormone therapy

Dutasteride is sometimes used as a component of hormone therapy for transgender women in combination with an estrogen and/or another antiandrogen such as spironolactone. [6] It may be useful for treating scalp hair loss or in those who have issues tolerating spironolactone. [6]

Available forms

Dutasteride is provided in the form of soft, oil-filled gelatin capsules containing 0.5 mg dutasteride each. [24]

Contraindications

Women who are or who may become pregnant should not handle the drug. Dutasteride can cause birth defects in male fetuses, specifically ambiguous genitalia and undermasculinization. [24] [25] This is due to its antiandrogenic effects similar to what is seen in 5α-reductase deficiency. [25] For the same reason, women who are currently pregnant should never take dutasteride. [24] People taking dutasteride should not donate blood to prevent birth defects if a pregnant woman receives blood and should also not donate blood for at least 6 months after the cessation of treatment due to the drug's long elimination half-life. [24]

Children and people with known significant hypersensitivity (e.g., serious skin reactions, angioedema) to dutasteride should not take it. [24]

Adverse effects

Dutasteride has overall been found to be well tolerated in studies of both men and women, producing minimal side effects. [26] Adverse effects include headache and gastrointestinal discomfort. [26] Isolated reports of menstrual changes, acne, and dizziness also exist. [26] A small risk of sexual side effects has been documented in men taking the drug during the first few months of therapy. [26] [27]

The FDA added a black-box warning to dutasteride in 2011 describing an increased risk of high-grade prostate cancer in those who take the drug. [28] No direct mechanistic link between 5α-reductase inhibitors and prostate cancer has been established. [29] This is not due to a direct link between dutasteride or other 5α-reductase inhibitors and cancer per se, but rather that those who take 5α-reductase inhibitors may have a decrease in prostate-specific antigen (PSA) levels, and therefore increases in PSA (which are an indicator of possible cancer) may be masked in those who take the drug. [30] This is thought to delay cancer diagnosis so that patients taking 5α-reductase inhibitors present with a higher-grade tumor at the time of diagnosis. The American Urological Association advises that increased risk for patients taking these drugs leads to higher prostate cancer-specific and all-cause mortality. [29] The AUA also advises that this affect can be alleviated with more frequent screening and lower PSA cutoffs for diagnostic biopsies in men taking dutasteride or other 5α-reductase inhibitors. [29] Dutasteride is known to reduce the growth and prevalence of benign prostate tumors. [31] A 2018 meta-analysis found no higher risk of breast cancer with 5α-reductase inhibitors. [32]

Sexual and mood side effects, such as erectile dysfunction, [33] loss of libido, [34] depression, [35] and reduced semen volume occur in as many as 4.8% of patients taking 5α-reductase inhibitors including dutasteride. [36] [34] In affected men, semen volume is decreased an average of 30%, [37] with a smaller subgroup of patients also experiencing a decrease of sperm motility of 6-12%. [38] [39] Sperm shape and function are unaffected and the impact on male fertility is unknown. [40] These negative effects reverse by 3–4 months after discontinuation of the drug. [40] [39] [29]

In a study of 6,729 men with benign prostatic hyperplasia (BPH, a condition where the prostate grows unnassociated with cancer), 9% had erectile dysfunction (compared to 5.7% treated with a placebo), 3.3% experienced decreased sex drive (vs 1.6% of placebo), and 1.9% had enlarged breasts (vs 1% of placebo). [33] [10] These effects were noted to resolve over time, with many fewer men reporting any adverse effects by the end of the 4-year study. [10] [33] The rate of discontinuation of the drug due to adverse effects was less than 5%. [10]

A subset of men affected by sexual and mood side effects report persistent loss of libido, [33] depression, [26] and erectile dysfunction for several years after discontinuing treatment. [34] This remains a highly contested topic in the academic literature due to disagreements about whether the nocebo effect may play a role, [41] [42] [43] whether self-report questionnaires are reliable for this data, [29] and whether enough objective evidence exists to conclude these effects are persistent after discontinuation of the drug. [29] [44] [45] The Post-Finasteride Syndrome Foundation (PFSF) was created with a medical advisory board to study the topic (finasteride is a similar 5α-reductase inhibitor) [46] and lawsuits alleging harm from the drug are ongoing. [47] Concerns from the PFSF and other patient advocates led the FDA to add a black-box warning to Finasteride for possible risks of suicide in June 2022. [29] [48] Some experts have questioned the basis of the black-box warning, given that it relies on anecdotal patient-reported outcomes rather than prospective trials. [29]

Overdose

No specific antidote for overdose of dutasteride is known, since the drug is extremely safe and well tolerated. Research studies show that even at 100 times the normal dose, dutasteride is not lethal. [49] Treatment of dutasteride overdose should be based on symptoms and should be with supportive therapies. [49] The long elimination half-life of dutasteride should be taken into consideration in the event of an overdose of the medication. [49] Dutasteride has been used in clinical studies at doses of up to 40 mg/day for a week (80 times the therapeutic dosage) and 5 mg/day for 6 months (10 times the therapeutic dosage) with no significant safety concerns or additional side effects. [49]

Current investigations

Dutasteride has been studied in combination with bicalutamide in the treatment of prostate cancer. [50] [51] [52]

Ongoing clinical trials are investigating whether dutasteride may be an effective treatment for premenstrual dysphoric disorder (PMDD), because dutasteride may inhibit the conversion of progesterone to allopregnanolone, a neurosteroid metabolite, which may be responsible for some of the debilitating symptoms of PMDD. [53] [54]

Pharmacology

Pharmacodynamics

Dutasteride belongs to a class of drugs called 5α-reductase inhibitors, which block the action of the 5α-reductase enzymes that convert testosterone into DHT. [55] It inhibits all three forms of 5α-reductase, and can decrease DHT levels in the blood by up to 98%. [1] [56] [57] Specifically it is a competitive, mechanism-based (irreversible) inhibitor of all three isoforms of 5α-reductase, types I, II, and III (IC50 Tooltip Half-maximal inhibitory concentration values are 3.9 nM for type I and 1.8 nM for type II). [1] [56] [58] [59] This is in contrast to finasteride, which is similarly an irreversible inhibitor of 5α-reductase but only inhibits the type II and III isoenzymes. [59] [60] [56] As a result of this difference, dutasteride is able to achieve a reduction in circulating DHT levels of up to 98%, whereas finasteride is able to achieve a reduction of only 65 to 70%. [57] [2] [55] [61] In spite of the differential reduction in circulating DHT levels, the two drugs decrease levels of DHT to a similar extent of approximately 85 to 90% in the prostate gland, [61] where the type II isoform predominates. [58]

Since 5α-reductases degrade testosterone to DHT, the inhibition of these enzymes could theoretically cause an increase in testosterone. A 2018 review found that initiation of 5α-reductase inhibitors did not result in a consistent increase in testosterone levels. [62] Among the studies analyzed, there was no statistically significant change in testosterone levels from 5α-reductase inhibitors overall, though men with lower baseline testosterone levels did show an increase. [62]

In addition to inhibition of DHT production, 5α-reductase inhibitors such as dutasteride are also neurosteroidogenesis inhibitors, preventing the 5α-reductase-mediated biosynthesis of various neurosteroids, including allopregnanolone (from progesterone), THDOC Tooltip tetrahydrodeoxycorticosterone (from deoxycorticosterone), and 3α-androstanediol (from testosterone). [36] These neurosteroids are potent positive allosteric modulators of the GABAA receptor and have shown antidepressant, anxiolytic, and pro-sexual effects in animal research. [36] [63] [64] For this reason, decreased neurosteroid production is one hypothesized mechanism for sexual dysfunction and depression associated with 5α-reductase inhibitors such as dutasteride. [36]

Pharmacokinetics

The oral bioavailability of dutasteride is about 60%. [1] Consumption with food does not adversely affect its absorption. [1] Peak plasma levels occur 2 to 3 hours after administration. [1] Dutasteride is present in semen at levels up to 3 ng/ml, with no significant effects on DHT levels of sexual partners. [1] The drug is extensively metabolized in the liver by CYP3A4 . [1] It has three major metabolites: 6'-hydroxydutasteride, 4'-hydroxydutasteride, and 1,2-dihydrodutasteride. The former two are formed by CYP3A4, while the latter is not. [1] All three metabolites are active; 6'-hydroxydutasteride has similar 5α-reductase inhibitor potency as dutasteride, while the other two are less potent. [1] Dutasteride has an extremely long terminal or elimination half-life of about 4 to 5 weeks. [2] [3] Its elimination half-life is increased in the elderly (170 hours for men aged 20–49 years, 300 hours for men aged >70 years). [1] No dosage adjustment is necessary in the elderly nor in patients with renal impairment. [1] Because of its long elimination half-life, dutasteride requires 5 to 6 months to reach steady-state concentrations. [58] It also remains in the body for a long time after discontinuation and can be detected up to 4 to 6 months. [1] [2] In contrast to dutasteride, finasteride has a short terminal half-life of only 5 to 8 hours. [3] [1] Dutasteride is eliminated mainly in the feces (40%) as metabolites. [1] A smaller portion (5%) is eliminated unchanged in the urine. [1]

Chemistry

Dutasteride, also known as N-[2,5-bis(trifluoromethyl)phenyl]-3-oxo-4-aza-5α-androst-1-ene-17β-carboxamide, is a synthetic androstane steroid and a 4-azasteroid. [65] [66] It is an analogue of finasteride in which the tert-butyl amide moiety has been replaced with a 2,5-bis(trifluoromethyl)phenyl group. [66]

History

Dutasteride was patented in 1996 and was first described in the scientific literature in 1997. [67] [68] It was approved by the FDA for the treatment of BPH in November 2001, and was introduced on the United States market the following year under the brand name Avodart. [68] Dutasteride has subsequently been introduced in many other countries, including throughout Europe and South America. [68] The patent protection of dutasteride expired in November 2015, so the drug has since become available in the United States in a variety of low-cost generic formulations. [67]

It was approved for the treatment of scalp hair loss in South Korea in 2009 and in Japan in 2015. [69] It has not been approved for this indication in the United States, [5] [16] though it is often used off-label. [20]

Society and culture

Avodart (dutasteride) 500 ug soft capsules Avodart.jpg
Avodart (dutasteride) 500 µg soft capsules

Generic names

Dutasteride is the generic name of the drug Avodart and its international nonproprietary name, United States Adopted Name, British Approved Name, and Japanese Accepted Name. [70]

Brand names

Dutasteride is sold primarily under the brand name Avodart, but also in combination with tamsulosin under the brand names Combodart, Duodart, and Jalyn. [70] Dutasteride is also available in India in combination with alfuzosin under the brand names Alfusin-D and Dutalfa. [70]

Availability

Dutasteride is available widely throughout the world, including in the United States, Canada, the United Kingdom, Ireland, Europe, Australia, South Africa, Latin America, Asia, and elsewhere. [70] It is available as a generic medication in many countries, including the United States. [67]

Related Research Articles

<span class="mw-page-title-main">Benign prostatic hyperplasia</span> Noncancerous increase in size of the prostate gland

Benign prostatic hyperplasia (BPH), also called prostate enlargement, is a noncancerous increase in size of the prostate gland. Symptoms may include frequent urination, trouble starting to urinate, weak stream, inability to urinate, or loss of bladder control. Complications can include urinary tract infections, bladder stones, and chronic kidney problems.

<span class="mw-page-title-main">Antiandrogen</span> Class of pharmaceutical drugs

Antiandrogens, also known as androgen antagonists or testosterone blockers, are a class of drugs that prevent androgens like testosterone and dihydrotestosterone (DHT) from mediating their biological effects in the body. They act by blocking the androgen receptor (AR) and/or inhibiting or suppressing androgen production. They can be thought of as the functional opposites of AR agonists, for instance androgens and anabolic steroids (AAS) like testosterone, DHT, and nandrolone and selective androgen receptor modulators (SARMs) like enobosarm. Antiandrogens are one of three types of sex hormone antagonists, the others being antiestrogens and antiprogestogens.

<span class="mw-page-title-main">Dihydrotestosterone</span> Human hormone

Dihydrotestosterone is an endogenous androgen sex steroid and hormone primarily involved in the growth and repair of the prostate and the penis, as well as the production of sebum and body hair composition.

<span class="mw-page-title-main">Finasteride</span> Antiandrogen medication

Finasteride, sold under the brand names Proscar and Propecia among others, is a medication used to treat pattern hair loss and benign prostatic hyperplasia (BPH) in men. It can also be used to treat excessive hair growth in women. It is usually taken orally but there are topical formulations for patients with hair loss, designed to minimize systemic exposure by acting specifically on hair follicles.

5α-Reductase Enzyme family

5α-Reductases, also known as 3-oxo-5α-steroid 4-dehydrogenases, are enzymes involved in steroid metabolism. They participate in three metabolic pathways: bile acid biosynthesis, androgen and estrogen metabolism. There are three isozymes of 5α-reductase encoded by the genes SRD5A1, SRD5A2, and SRD5A3.

<span class="mw-page-title-main">5α-Reductase inhibitor</span> Class of medications

5α-Reductase inhibitors (5-ARIs), also known as dihydrotestosterone (DHT) blockers, are a class of medications with antiandrogenic effects which are used primarily in the treatment of enlarged prostate and scalp hair loss. They are also sometimes used to treat excess hair growth in women and as a component of hormone therapy for transgender women.

<span class="mw-page-title-main">Pattern hair loss</span> Medical condition

Pattern hair loss is a hair loss condition that primarily affects the top and front of the scalp. In male-pattern hair loss (MPHL), the hair loss typically presents itself as either a receding front hairline, loss of hair on the crown (vertex) of the scalp, or a combination of both. Female-pattern hair loss (FPHL) typically presents as a diffuse thinning of the hair across the entire scalp.

Masculinizing hormone therapy, also known as transmasculine hormone therapy or female-to-male hormone therapy, is a form of hormone therapy and gender affirming therapy which is used to change the secondary sexual characteristics of transgender people from feminine or androgynous to masculine. It is a common type of transgender hormone therapy, and is predominantly used to treat transgender men and other transmasculine individuals who were assigned female at birth. Some intersex people also receive this form of therapy, either starting in childhood to confirm the assigned sex or later if the assignment proves to be incorrect.

Feminizing hormone therapy, also known as transfeminine hormone therapy, is hormone therapy and sex reassignment therapy to change the secondary sex characteristics of transgender people from masculine or androgynous to feminine. It is a common type of transgender hormone therapy and is used to treat transgender women and non-binary transfeminine individuals. Some, in particular intersex people, but also some non-transgender people, take this form of therapy according to their personal needs and preferences.

<span class="mw-page-title-main">Epristeride</span> Chemical compound

Epristeride, sold under the brand names Aipuliete and Chuanliu, is a medication which is used in the treatment of enlarged prostate in China. It is taken by mouth.

Sexual motivation is influenced by hormones such as testosterone, estrogen, progesterone, oxytocin, and vasopressin. In most mammalian species, sex hormones control the ability and motivation to engage in sexual behaviours.

A neurosteroidogenesis inhibitor is a drug that inhibits the production of endogenous neurosteroids. Neurosteroids include the excitatory neurosteroids pregnenolone sulfate, dehydroepiandrosterone (DHEA), and dehydroepiandrosterone sulfate (DHEA-S), and the inhibitory neurosteroids allopregnanolone, tetrahydrodeoxycorticosterone (THDOC), and 3α-androstanediol, among others. By inhibiting the synthesis of endogenous neurosteroids, neurosteroidogenesis inhibitors have effects in the central nervous system.

A steroidogenesis inhibitor, also known as a steroid biosynthesis inhibitor, is a type of drug which inhibits one or more of the enzymes that are involved in the process of steroidogenesis, the biosynthesis of endogenous steroids and steroid hormones. They may inhibit the production of cholesterol and other sterols, sex steroids such as androgens, estrogens, and progestogens, corticosteroids such as glucocorticoids and mineralocorticoids, and neurosteroids. They are used in the treatment of a variety of medical conditions that depend on endogenous steroids.

<span class="mw-page-title-main">Nandrolone phenylpropionate</span> Anabolic steroid

Nandrolone phenylpropionate (NPP), or nandrolone phenpropionate, sold under the brand name Durabolin among others, is an androgen and anabolic steroid (AAS) medication which has been used primarily in the treatment of breast cancer and osteoporosis in women. It is given by injection into muscle once every week. Although it was widely used in the past, the drug has mostly been discontinued and hence is now mostly no longer available.

<span class="mw-page-title-main">Testosterone (medication)</span> Medication and naturally occurring steroid hormone

Testosterone (T) is a medication and naturally occurring steroid hormone. It is used to treat male hypogonadism, gender dysphoria, and certain types of breast cancer. It may also be used to increase athletic ability in the form of doping. It is unclear if the use of testosterone for low levels due to aging is beneficial or harmful. Testosterone can be used as a gel or patch that is applied to the skin, injection into a muscle, tablet that is placed in the cheek, or tablet that is taken by mouth.

<span class="mw-page-title-main">5α-Dihydronandrolone</span> Chemical compound

5α-Dihydronandrolone is a naturally occurring anabolic–androgenic steroid (AAS) and a 5α-reduced derivative of nandrolone (19-nortestosterone). It is a major metabolite of nandrolone and is formed from it by the actions of the enzyme 5α-reductase analogously to the formation of dihydrotestosterone (DHT) from testosterone.

<span class="mw-page-title-main">MK-386</span> Chemical compound

MK-386, also known as 4,7β-dimethyl-4-aza-5α-cholestan-3-one, is a synthetic, steroidal 5α-reductase inhibitor which was first reported in 1994 and was never marketed. It is a 4-azasteroid and a potent and selective inhibitor of 5α-reductase type I and shows high selectivity for inhibition of human 5α-reductase type I over 5α-reductase type II, with IC50 values of 0.9 nM and 154 nM, respectively. The drug was under investigation for potential treatment of androgen-dependent conditions such as acne and pattern hair loss (androgenic alopecia or baldness), but was discontinued in early clinical trials due to observations of hepatotoxicity such as elevated liver enzymes.

This article is about the discovery and development of 5α-reductase inhibitors (5-ARIs), also known as dihydrotestosterone (DHT) blockers.

<span class="mw-page-title-main">MK-434</span> Chemical compound

MK-434 is a 5α-reductase inhibitor which was under development in the 1990s by Merck & Co for the treatment of a variety of androgen-dependent conditions including benign prostatic hyperplasia, prostate cancer, pattern hair loss, excessive hair growth, acne, and seborrhea but was never marketed. It acts as a selective inhibitor of 5α-reductase type 2. The drug has been found to decrease circulating dihydrotestosterone levels by a maximum of approximately 50% in men. MK-434 is a synthetic 4-azasteroid and is structurally related to other 5α-reductase inhibitors like finasteride.

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